This proposal is to prepare small molecules that will inhibit the protein-protein interaction between a protein called PCSK9 and the LDLR receptor. This is an extremely well validated target for reduction of bad cholesterol (LDL), and therefore controlling coronary artery disease. Orally available small molecules are the preferred therapeutic modality for this target, many companies have attempted to find ones that can inhibit PCSK9?LDLR receptor (usually via high through-out screening, HTS), yet no effective compounds have been reported to date. Small Molecule PPI Mimics LLC (PPI Mimics) owns intellectual property covering an innovative approach to designing small ligands that can perturb PPIs. The core of this approach is a proprietary strategy called Exploring Key Orientations (EKO) that facilitates data mining of structurally characterized PPIs on a massive scale to identify patentable scaffolds to perturb a specific PPI, or PPIs that can be perturbed by specific scaffolds. PPI Mimics is generating revenue by identifying patentable chemotypes that can be used to target commercially valuable PPIs in collaboration with pharmaceutical partners and in the longer term plans to expand the scope of their income streams by preparing and testing patentable chemotypes that the company will develop internally. In preliminary work, an academic partner has: (i) applied the EKO strategy to PCSK9?LDLR; (ii) identified a chemotype to putatively inhibit this interaction; and, (iii) developed a general synthetic scheme for that scaffold. This proposal seeks funds to make and test appropriate compounds in that chemotype series (the ones made so far are model compounds), and to publish this data to advertise the EKO technique and PPI Mimics' interest in PCSK9?LDLR. This will provide proof of principle that the EKO strategy can be used to identify compounds to inhibit PCSK9?LDLR. Simultaneously, PPI Mimics will use the EKO strategy to identify other chemotypes, owned by the company, that can be prepared and thoroughly evaluated in Phase 2.